Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2010, Article ID 697158, 12 pages doi:10.1155/2010/697158
Review Article Vaccines and Immunotherapeutics for the Treatment of Malignant Disease Joel F. Aldrich,1 Devin B. Lowe,1 Michael H. Shearer,1 Richard E. Winn,1, 2 Cynthia A. Jumper,1, 2 and Ronald C. Kennedy1, 2 1 Department
of Microbiology and Immunology, Texas Tech University Health Sciences Center, 3601 4th Street, MS 6591, Lubbock, TX 79430, USA 2 Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9410, Lubbock, TX 79430, USA Correspondence should be addressed to Ronald C. Kennedy,
[email protected] Received 14 May 2010; Accepted 25 August 2010 Academic Editor: Dennis Klinman Copyright © 2010 Joel F. Aldrich et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The employment of the immune system to treat malignant disease represents an active area of biomedical research. The specificity of the immune response and potential for establishing long-term tumor immunity compels researchers to continue investigations into immunotherapeutic approaches for cancer. A number of immunotherapeutic strategies have arisen for the treatment of malignant disease, including various vaccination schemes, cytokine therapy, adoptive cellular therapy, and monoclonal antibody therapy. This paper describes each of these strategies and discusses some of the associated successes and limitations. Emphasis is placed on the integration of techniques to promote optimal scenarios for eliminating cancer.
1. Introduction As cancer progresses toward the leading cause of death in the Unites States, physicians and biomedical scientists continue to explore novel therapeutic strategies outside the current standard of treatment. Despite the successes of surgery, radiation, chemotherapy, and a combination thereof in limiting the progression of malignant disease, these treatment methods often fail to elicit complete tumor remission and are associated with some debilitating side effects. In recent years, much attention has been paid to immunotherapy, which attempts to direct the protective capacity of the immune system toward eliminating malignancies. Harnessing the immune system to treat malignant disease is a powerful tool, not only due to the specificity of the immune response, but also due to the potential for establishing long-lasting tumor immunity via the capacity to exhibit memory. The ability of the immune system to destroy tumorigenic cells was first proposed by Macfarlane Burnet in the 1950s [1]. Some years later, Burnet coined the term “immune surveillance” to describe the function of the immune system in eliminating transformed cells both
before and after tumor formation [2]. A seminal study conducted by Shankaran and colleagues in 2001 confirmed the importance of certain immune components in limiting the formation of tumors in experimental animals. In this study, immunocompromised mice were found to be significantly more susceptible to spontaneous and carcinogeninduced primary tumor development than immunocompetent mice [3]. The critical role of the immune system in minimizing malignancies engenders profound sequelae in the human situation as well. Certain immunodeficiency disorders, including AIDS, are strongly associated with an increased risk of cancer [4]. Additionally, the formation of tumors in immunosuppressed organ transplant patients and among individuals receiving stem-cell transplants has been well documented and represents a major obstacle to the long-term success of these procedures [5]. Collectively, such findings provide an impetus for continual investigation of the therapeutic potential of antitumor immune responses. Immunotherapeutic strategies can be categorized broadly into two groups: active immunotherapy and passive immunotherapy. Establishing active immunity against tumors is a promising but inherently difficult task, and necessitates
2 a keen understanding of the multiple immunosuppressive mechanisms that the tumor microenvironment may exploit. According to Waldmann, maximizing the efficacy of active immunotherapy will require a thorough investigation of the appropriate target antigens; the optimal interactions between lymphocytes, antigen-presenting cells (APC), and antigens; and the obstruction of negative immune regulation [6]. Although this immunotherapeutic strategy holds the potential for establishing long-lasting tumor immunity, the dissolution of immune tolerance to prospective cancer antigens remains a challenging and controversial process. The possibility of eliciting rampant autoimmunity in the wake of tumor reactive lymphocytes remains a key concern in the ultimate utility of active immunotherapy, particularly when this therapy is used in combination with other immunostimula- tory techniques [7, 8]. Passive immunotherapy using clonally expanded tumorspecific T cells represents a different approach to manipulating components of the host’s immune system to target cancer. Unlike active approaches, tumor-specific lymphocytes are expanded ex vivo, allowing for more direct manipulations of the prospective immune effectors. As with active immunotherapy, however, the possible longterm effects of harboring self-reactive lymphocytes warrants further assessment. Additionally, passive immunotherapy using monoclonal antibodies (MAbs) and immunoglobulin (Ig)-fusion proteins is a rapidly emerging technology that holds great potential for effectively treating malignant disease. The increasing incidence of MAb therapy in the treatment of cancer and other diseases firmly establishes the legitimacy of such molecules as effectual and specific anticancer agents [9]. A total of nine MAbs and modified Ig molecules have been approved by the FDA for use in cancer patients, and many more are in the process of clinical trials. Despite the enthusiasm for this type of therapy, several key challenges still remain for optimizing the efficacy of these artificial immune effectors. Such challenges include minimizing the induction of host-neutralizing antibody responses and curtailing the residual cytotoxicity of some Igfusion molecules. Additionally, both vaccination and MAb approaches to tumor immunotherapy may encourage the generation of tumor cells that evade immune recognition. In accordance with the process of “immunoediting,” tumor cells that bear antigenic targets for vaccination or MAb therapy are subject to destruction; however, tumors may compensate by expanding populations of antigenically undetectable tumor cells [10, 11]. These “immune escape variants” arise due to selective pressures imparted on the tumor microenvironment by antigen-specific immunotherapies, and subsist via the strategic masking of antigens that are recognized by the antitumor immune response.
2. Vaccination As an Immunotherapeutic Tool 2.1. Identification of Appropriate Tumor Antigens. Given the historic success of active immunization in protecting against infectious microbial diseases, many researchers are attempting to apply vaccination approaches to cancer
Clinical and Developmental Immunology immunotherapy. Indeed, several prophylactic vaccines have been generated against viral infectious agents that are also causative for certain human cancers. FDA-approved vaccines against hepatitis B virus (HBV) and human papilloma virus (HPV) are associated with protection against HBVinduced liver cancer and HPV induced cervical carcinomas, respectively. This clearly demonstrates that vaccines can be produced to prevent human malignancies. There are several vaccine modalities currently under investigation, including protein/peptide vaccines, ex-vivo loaded dendritic cells (DCs), DNA vaccines, and recombinant viral/bacterial vectors expressing particular tumor antigens. Additionally, prime-boost vaccine strategies seek to optimize the immune response by combining two or more of these modalities into a single treatment regimen. Common prime-boost strategies include primary immunization with plasmid DNA and subsequent immunizations with recombinant protein or viral vectors, although considerable variations on this theme abound within the literature [12]. The ultimate intention of immunization is induction of a tumor-specific immune response, thus the identification of appropriate tumor antigens remains a key concern for each of these vaccine strategies. Among the various categories of candidate antigens, tumor-specific antigens represent ideal targets, as these molecules are expressed exclusively on tumor cells. Examples of tumor-specific antigens include the products of mutated oncogenes and altered tumor suppressor proteins. One such tumor suppressor protein is p53, which plays a critical role in regulation of the cell cycle and is a target of some oncogenic viral proteins, including Tax from human T-cell lymphotropic virus-1 (HTLV-1) [13] and large T antigen (Tag) from simian virus 40 (SV40) [14]. Despite numerous reports of detectable humoral responses against p53 in cancer patients, the protection afforded by such responses appears to be minimal [15]. Additionally, the limited propensity for oncogenic mutants of normal cellular genes to promote the generation of protective cytotoxic T lymphocyte (CTL) responses presents a major obstacle to the exploitation of these antigens [16]. Within the last decade, several tumor-specific self-antigens that are recognized by CTLs have been identified (including CDK-4, β-catenin, and Caspase-8), and show potential for incorporation into cancer vaccines [17]. In addition to tumor-specific self-antigens, viral oncoproteins represent a unique class of tumor antigen that, during the course of viral infection, may be expressed primarily on transformed cells and infected cells harboring an increased neoplastic potential. A study performed by Duraiswamy and colleagues in 2003 provided convincing evidence of the ability for a polyepitope vaccine directed against the latent membrane protein 1 (LMP1) of EpsteinBarr virus (EBV) to provide immunity against aggressive tumors expressing LMP1 in mice [18]. Importantly, the tumor immunity evoked in this model was observable both in a prophylactic setting and in a therapeutic vaccine scenario. Such findings continue to compel researchers to investigate vaccination schemes that target viral oncoproteins as tumor-specific antigens. Indeed, the efficacy of both SV40 Tag recombinant protein and SV40 Tag DNA vaccines in
Clinical and Developmental Immunology protecting mice against Tag expressing tumors has been well documented by our laboratory [19]. While only a few viruses have been directly implicated in the generation of tumors in humans (namely HTLV, EBV, and HPV), the pathology associated with certain other viruses, including human immunodeficiency virus (HIV), HBV, and hepatitis C virus (HCV), may promote the development of tumors in some individuals. Certain viruses may also act synergistically to provoke tumorigenesis; for example, coinfection with Kaposi’s sarcoma-associated herpesvirus and HIV often results in the formation of disseminated blood vessel tumors. In addition to viral pathogens, gastric inflammation induced by the bacterium Helicobacter pylori has been suggested to encourage the growth of local tumors. Accordingly, vaccines that eliminate these oncogenic and prooncogenic microbes may provide protection against malignant disease prior to the formation of tumor foci. Unfortunately, many types of cancer do not express universally recognized antigens that are associated exclusively with tumor cells. Investigators must therefore explore the use of other antigens that are expressed differentially on normal and cancerous cells. Various categories of tumor associated antigens (TAAs) have been described, including overexpressed self-antigens, differentiation antigens, and antigens from immune privileged sites (cancer/testes antigens) [17]. The first TAA to be identified was MAGE-1, which is an antigen expressed in tumor cells and germ cells and is prone to recognition by CTLs [20]. The absence of MAGE expression in most normal adult tissues (including liver, muscle, skin, lung, brain, and kidney), and the relative abundance of this antigen in tumors and germline tissues (e.g., testis, placenta, ovary), qualifies MAGE as a classic cancer/testes (CT) antigen. Moreover, vaccines that target CT antigens are unlikely to cause collateral tissue destruction, as normal adult cells are not transcriptionally active for CT antigens and germ cells lack the necessary machinery for antigen presentation to the immune system. Other major TAA categories include differentiation antigens, of which the melanocyte proteins tyrosine and MART are examples, and overexpressed self-antigens, of which the common breast cancer antigen HER-2/neu (ErbB2) is an example. These antigens are thought to be expressed by such a small group of cells and/or in such limited quantities, that the immune system fails to induce tolerance to these self proteins. Several prospective self-antigens have thus been identified for use in cancer immunotherapy [21], with some of the more common antigens listed in Table 1. 2.2. Vaccination Strategies. Although protein/peptide vaccination with purified antigen plus adjuvant has long served as an effective vaccine strategy in the prevention of microbial disease, recent advances in the field of vaccine development may favor the use of DNA-based or APC-based vaccines in the treatment of malignant disease. Despite numerous studies that have demonstrated the antitumor potential of conventional recombinant protein vaccination, this vaccine modality may curtail antigen presentation through the major histocompatibility complex (MHC) class I pathway and elicit
3 a predominantly humoral immune response [22]. Since CTLs are commonly thought to comprise the major effector cell type in tumor immunity, vaccination methods that enhance cell mediated immune responses may prove optimal for use in cancer immunotherapy. In the early 1990s, Wolff and colleagues reported that transgene expression in mice could be accomplished upon direct injection of naked plasmid DNA into mammalian muscle tissue [23]. Subsequently, Ulmer and colleagues used another murine model to demonstrate the utility of DNA vaccines as a preventative against heterologous influenza virus infection [24]. Translational studies targeting HIV and malarial antigens commenced in the late 1990s, and soon established the safety of this vaccination scenario in humans [25–27]. Within the last decade, experimental DNA vaccination in dogs has demonstrated the efficacy of this vaccine modality in prolonging survival time within the context of aggressive malignant disease. In one important study, dogs suffering from canine malignant melanoma were immunized therapeutically with plasmid DNA encoding human tyrosinase, which is approximately 91% identical to canine tyrosine [28]. The median survival time of dogs in this study was 389 days; substantially higher than the
